Acyl coenzyme A: cholesterol acyltransferase (ACAT) is an enzyme which catalyzes synthesis of cholesterol ester from cholesterol, and it plays an important role in the metabolism of the cholesterol and its absorption from the digestive tract.
Recent studies have revealed that elevation of blood cholesterol level can be effectively suppressed by inhibiting the activity of ACAT in small intestine and liver, and quite a number of studies have been conducted on ACAT inhibitor.
On the other hand, the present inventors focused the study on ACAT in vascular wall, and studied on the selective inhibitors against this type of ACAT. It was then found that azole compounds having a cyclic diamine structure, and in particular, a cyclic diamine compound represented by the following formula (7):
wherein Ar represents an optionally substituted aryl or heteroaryl group, as well as its salt exhibit reduced side effects, high solubility in water, and excellent oral absorption, and that such compound is well adapted for use as a therapeutic drug for hyperlipidemia and arteriosclerosis. As a result, the present inventors have filed a PCT application for an invention associated with azole compounds including the compound (7) (WO98/54153).
This patent application has demonstrated that the compound (7) can be produced by the method as represented by the following reaction scheme.

In this method, the compound (7) is produced in the five steps as described below by starting from 1-(2-hydroxyethyl) piperazine (6), namely,
by protecting amino group of the 1-(2-hydroxyethyl) piperazine (6) with tert-butoxycarbonyl (Boc) group to produce 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl) piperazine (1a) (Step a); converting hydroxyl group of this compound (1a) to methanesulfonyloxy group to produce compound (2a) (Step b); reacting this compound (2a) with 2-mercaptobenzimidazole (3) in the presence of a base to produce 1-[2-(benzimidazol-2-ylthio)ethyl]-4-(tert-butoxycarbonyl) piperazine (4a) (Step c); removing the Boc group for deprotection by using trifluoroacetic acid to produce 1-[2-(benzimidazol-2-ylthio)ethyl]piperazine.3 trifluoroacetic acid (5a) (Step d); and reacting the compound (5a) with a bromo derivative (8) to thereby produce the compound (7) or its salt (Step e).
This production method, however, suffered from the problems including (i) di-tert-butyl dicarbonate, which is the expensive reagent used in the amino group protection; (ii) difficulty in Step a of purifying the target compound (1a) by distillation, which is the convenient purification method; (iii) difficulty of producing the compound (1a) in highly anhydrous condition as required by the following Step b because of the difficulty in the purification by distillation; (iv) poor stability of the mesyl derivative (2a) which is used as the starting material in Step c, and difficulty in reproducing the yield of the small scale synthesis in the large scale synthesis; and (v) insufficient yield in the deprotection reaction of Step d.